Many diseases of the nervous system are now thought to involve breakdowns in communication among neurons within and between brain regions. The conventional model for the flow of activity in neural networks is that synaptic inputs from neurons at one stage of processing are summed by any given neuron in the next stage. In reality though, synapses are made onto long, branching dendritic trees that can have complicated effects on normal integration of synaptic inputs. First, the dendritic membrane itself attenuates any synaptically-evoked electrical signal being conducted along the tree to the cell body. Diminished signals may be less likely to contribute to a neuronal discharge and to activate downstream synapses onto other neurons. Second, the coincident activation of several neighboring synapses can open specialized voltage-gated channels in the cell membrane, generating a dendritic "spike" in membrane potential larger than the sum of the individual synaptic signals. The aims of this project are to understand how each of these two dendritic properties affect cortical activity and processing of sensory stimuli, with a focus on the initial stages of processing in neocortex. Processing is thought to begin with sensory information from the outside world entering sensory cortex via thalamocortical synapses from thalamus to cortical layer 4. Thalamocortical synapses are thought to be individually stronger than corticocortical synapses. The first aim is to test whether thalamocortical synapses onto a cortical dendritic tree are closer to the cell body, a potential mechanism for the greater relative efficacy of thalamocortical connections. Correlative confocal and electron microscopy will be used to map the locations of synapses across the dendritic trees of cortical neurons. Receptive fields of labeled pairs of individual thalamic and cortical neurons will be measured to ask if dendritic attenuation contributes to how cortical neurons are tuned to particular sensory stimuli. The second aim is to ask if dendritic spikes boost the ability of thalamocortical synapses to directly activate cortical neurons. This will be tested by combining intracellular recording in vivo with pharmacological blockade of voltage-gated channels or individual cortical layers. Confocal microscopy will additionally be used to test whether thalamocortical synapses are sufficiently clustered along cortical dendrites to engage dendritic spikes. If these aims show that synaptic location is important, subtle mistargeting of synapses by dysfunctional genetic or activity-dependent mechanisms would lead to abnormal flow of excitation between brain regions, potentially initiating or contributing to seizure- or tremor-like activity in neurological diseases. PUBLIC HEALTH RELEVANCE: This study will address how dendritic mechanisms of neurons influence the propagation of excitation from one brain region to the next. The results will contribute to our understanding of cellular mechanisms that, when disrupted, may produce seizures, tremors, and other neurological pathology. These goals are compatible with NINDS'Blue Sky strategic planning efforts by mapping out the connectivity of the healthy nervous system, both anatomically and functionally, and identifying cellular mechanisms that may be targeted in the treatment of neurodegenerative disorders.